Infect and inject: How mycobacterium tuberculosis exploits its major virulence-associated type VII secretion system, ESX-1

Tuberculosis (TB) is a global health problem caused by the airborne pathogen Mycobacterium tuberculosis. Currently, one-third of the world’s population is infected with M. tuberculosis, and this slow, tenacious bacterium kills 1.6 million people around the world each year, equating to over 4,300 deaths every day (1). Failure to eradicate this age-old disease is the result of an ineffective vaccine and extended, often insufficient, chemotherapy. To date, the only licensed vaccine available is Mycobacterium bovis BCG, a live attenuated strain of M. bovis discovered in 1919 by Albert Calmette and Camille Guérin following 230 subcultures of the original virulent isolate (2, 3). Distribution of this vaccine to various countries, and more subculturing, led to genetic variations between different BCG strains. However, all strains possess a common deletion that occurred prior to 1919. The deleted region is called region of difference 1 (RD1), and it encodes a key part of the type VII secretion system known as ESAT-6 secretion system 1 (ESX-1) (Fig. 1A); deletion(s) in this particular region are considered the major cause of BCG attenuation (4-6).